We have engaged in a long-term effort to characterize the role of the HIV envelope protein (gp120/41) in the pathogenesis of HIV disease. This effort has included biological and biochemical characterizations of the interaction between the HIV envelope and cell surface receptors, as well as the role of envelope-mediated signals in pathogenesis. We have identified a new interaction between gp120 and integrin alpha4beta7. The function of alpha4beta7 is intimately linked to gut associated lymphoid tissue, a principal site of HIV replication, suggesting that envelope-alpha4beta7 interactions play an important role in HIV pathogenesis. We determined that alpha4beta7high CD4+ T cells are more susceptible to productive infection by HIV than are alpha4beta7low-neg CD4+ T cells, in part because the former cellular subset is enriched with metabolically active cells. We found that on these cells, alpha4beta7 appears in a complex with the CD4 receptor. We hypothesized that the specific affinity of gp120 for alpha4beta7 provides a mechanism for HIV to target metabolically active CD4+ T cells and that such an activity might prove critical for efficient virus propagation and dissemination following mucosal transmission.